Activated Akt signaling is a significant contributor to the pathogenesis of breast cancer. PTEN is a negative regulator of PI3K/Akt signaling and is decreased in breast cancer. Over 20% of breast cancers have mutations in PIK3CA, the p110alpha catalytic subunit of PI3K, with Akt-dependent and independent downstream effects. MK2206 is a selective allosteric inhibitor of Akt. In vitro and in vivo, many of the PIK3CA mutant cell lines and cell lines with PTEN loss are sensitive to MK2206. We hypothesize that Akt inhibitor MK2206 has antitumor activity in advanced breast cancer patients who have tumors with a PIK3CA mutation and/or PTEN loss, and that baseline markers and early pharmacodynamic changes in tumor and blood can predict clinical benefit. In aim 1, we will determine whether MK2206 has anti-tumor activity in a CTEP-approved Phase II multicenter trial in patients with metastatic, or unresectable locally advanced, or locally recurrent breast cancer with PIK3CA mutations and/or PTEN loss. We will determine whether MK2206 achieves objective tumor responses and determine the 6 month progression-free survival. We will determine whether MK2206 decreases cell proliferation and/or increases apoptosis after two weeks of treatment. In Aim 2, we will determine baseline and pharmacodynamic markers in tumor tissue and blood that may predict outcome. We will determine whether MK2206 inhibits Akt signaling, and if this correlates with a decline in Ki-67, increase in apoptosis, and clinical benefit. We will determine whether baseline activation of Akt signaling (as determined by proteomic and transcriptional signatures) correlate with clinical benefit. We will determine whether decrease in Ki-67 and/or increase in apoptosis at 2 weeks correlate with benefit. We will compare the effect of MK2206 on the tumor and in peripheral blood mononuclear cells and platelets. Public Health Relevance: Breast cancer is a major public health problem. Activated Akt signaling is mediator of resistance to some of the existing breast cancer therapies. We will determine whether MK2206 has antitumor activity in patients with PI3KCA mutations or PTEN loss. We will determine whether MK2206 indeed inhibits Akt in clinically tolerated doses, and we will perform exploratory studies to identify predictors and pharmacodynamic markers of response. These studies will elucidate which breast cancer populations are most likely to benefit from MK2206. As Akt is activated in many cancers, are results will have implications for patients with several other cancer types.